tbuckley/cabot-search huggingface dataset:
Abstract 1145: Therapeutic drug monitoring of Sunitinib in real-world patients
Authors: Laurent Ferrer, Jonathan Chauvin, Dr Jean-Laurent Deville, Joseph Ciccolini
Journal: Cancer Research (2022)

Abstract Therapeutic Drug Monitoring (TDM) with model-based adaptive dosing is expected to quickly ensure that exposure levels of anticancer agents are in the adequate range of plasma concentrations. Here, we have compared such TDM + in silico approach with empirical changes in dosing performed upon clinical signs in patients with metastatic renal cell carcinoma treated with Sunitinib. A total of 31 patients were monitored in our institute. All patients were treated with a standard starting dose of 50 mg QD following the 4/2 schedule. Sunitinib and n-desethyl sunitinib trough levels were assayed at steady state by a fully validated LC-MS/MS analysis. A PK-pop model with Bayesian estimate implemented on Monolix helped to identify individual PK parameters from a single time-point. Two different target exposures were considered (i.e., trough levels comprised between 50 and 100 ng/ml or 0-24h AUC comprised between 1250 and 2150 ng/ml.h). The PK model enabled to simulate both trough levels and 0-24h AUC from a single sample, regardless of the sampling time. Overall, dosing was modified empirically in about 54% of the patients after treatment started, mostly (46%) for reducing the dosing after that toxicities showed. Clinical benefit (i.e., stable disease + partial response + complete reponse) was achieved in 54% of patients but treatment discontinuation was observed in 58% of the patients eventually, mostly because of severe side-effects. A relationship between baseline exposure levels and early onset treatment-related toxicities was found. Because of the various changes in dosing, no such relationship was found between baseline exposure levels and efficacy evaluated at 3 months. TDM showed that only 45% of the patients were in the right window for trough levels (i.e., 50-100 ng/ml) and only 26% when considering AUC as the target exposure (i.e., 1200-2150 ng/ml.h). Consequently, the PK/PD model would have suggested to rapidly customize dosing in a much larger part of the patients (i.e., 84% with respect to the target AUCs). Importantly, Sunitinib dosing was empirically reduced only in 41% patients who displayed early-onset severe toxicities, whereas modelling would have immediately proposed to cut the dosing in more than 80% of those patients, thus suggesting that the safety of Sunitinib could have been improved when using our model. Although performed on a limited number of patients, this real-world study supports the hypothesis that TDM associated with PK modelling could help the prescriber to identify the best Sunitinib dosing in a quicker way than empirical change in dosing. Citation Format: Laurent Ferrer, Jonathan Chauvin, Dr Jean-Laurent Deville, Joseph Ciccolini. Therapeutic drug monitoring of Sunitinib in real-world patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1145.
Abstract 4093: COSMIC Actionability: Supporting precision oncology through Identification of actionable mutations from clinical trials databases and publications
Authors: Steven C. Jupe, Nidhi Bindal, Zbyslaw Sondka, Shicai Wang, Sumodh Nair, Laura Ponting, Doron Sondheimer, Charlie Hathaway, Simon A. Forbes
Journal: Cancer Research (2022)

Abstract The availability of drugs that are effective in cancer patients with specific somatic mutations is rapidly evolving. Finding the most recent information is not straightforward; clinical progress and drug approvals are recorded in clinical trial repositories, files from drug regulatory agencies, publications and conference abstracts. Often there is a delay between trials reaching their outcomes, publication and deposition of results in clinical trial databases. COSMIC Actionability is a new addition to COSMIC’s (Catalogue Of Somatic Mutations In Cancer) portfolio of navigational databases for precision oncology. It indicates the availability of drugs that target mutations and tracks the progress of novel drugs through clinical development. All stages of drug development are represented, through safety and clinical efficacy to market approval, with additional data from case studies expanding mutation coverage. For each mutation-cancer type combination, a simple tiered system indicates whether marketed drugs are available and if not, indicates the progress of drug development efforts. Trial records available in databases such as Clinical Trials.gov and EudraCT are supplemented with trials identified in publications. Trial progression and outcomes are recorded; details are sourced from clinical trial databases, publications, conference abstracts, corporate announcements and regulatory authorities such as the FDA. Curation identifies results for approximately 40% more trials than are available in clinical trial databases alone. Like other COSMIC resources, Actionability is manually curated by Ph.D. level experts. The current version of COSMIC Actionability (October 2021) has 49 fully curated genes with a further 237 having some clinical information. Details of 6244 drug-cancer type combinations are available, of which 2224 have clinical results. 963 drugs are represented, in 2224 treatment combinations. 149 point mutations and 520 further mutations or fusions are represented. This dataset will be made freely available in 2022 then released quarterly, with extended gene coverage and updates of previous content. Citation Format: Steven C. Jupe, Nidhi Bindal, Zbyslaw Sondka, Shicai Wang, Sumodh Nair, Laura Ponting, Doron Sondheimer, Charlie Hathaway, Simon A. Forbes. COSMIC Actionability: Supporting precision oncology through Identification of actionable mutations from clinical trials databases and publications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4093.
Abstract 1581: Uncovering mechanisms of biogenesis and secretion of small extracellular vesicles in non small cell lung cancer (NSCLC)
Authors: Zulaida M. Soto Vargas, Ikjot Singh Sohal, Humna Hasan, David Arteaga, Andrea L. Kasinski
Journal: Cancer Research (2022)

Abstract Non-small cell lung cancer (NSCLC), the most common type of lung cancer, is the leading cause of cancer related deaths in United States. Only 24% of NSCLC patients survive 5-years post diagnosis, which could be attributed to the lack of efficient treatment strategies at the metastatic stage. Thus, understanding the biological mechanisms that promote NSCLC metastasis is critical for developing effective cancer-specific therapeutic agents. The development of cancer metastasis is greatly driven and influenced by intercellular communication. Key mediators of cell-to-cell communication are small extracellular vesicles (sEVs) of approximately 100-150 nm in diameter, often referred as exosomes. Previous report revealed that increased levels of exosomes in NSCLC patients correlated with lower overall survival. Indeed, secretion of sEVs by cancer cells can induce malignant transformation of non-cancerous cells nearby or at distant locations through influencing pre-metastatic niche formation. Therefore, biogenesis and release of cancer derived sEVs are determinant steps for the development of tumor metastasis. However, the mechanisms through which sEVs are produced and secreted by cancer cells are yet to be determined. Here, we isolated and characterized sEVs from a panel of NSCLC cell lines (H358, Calu6, H460, SKMES-1) and non-tumorigenic cells (BEAS-2B and HBEC) to identify mechanisms involved in the elevated secretion of EVs by cancer cells. Contrary to what has been previously reported in literature, our data demonstrated that not all cancer cell lines release high levels of sEVs. Our data suggests that elevated secretion of sEVs could be driven by specific mutations and oncogenic signaling in cancer cells. Among all the cell lines tested, H358 cells which harbor the infamous G12C mutation in KRAS, had the highest sEV release. Therefore, we hypothesize that the KRASG12C can drive high sEV production and secretion in H358 cells. Our preliminary data suggests that siRNA mediated knockdown of oncogenic KRAS signaling in H358 cells significantly decreases secretion of sEVs. Ongoing studies aim to pinpoint the detailed mechanisms by which cancer cells utilize KRAS oncogenic signaling to promote EV biogenesis pathways and tumorigenesis. The current study will provide the foundation to developed new therapeutic strategies against tumor sEVs-driven metastasis. Citation Format: Zulaida M. Soto Vargas, Ikjot Singh Sohal, Humna Hasan, David Arteaga, Andrea L. Kasinski. Uncovering mechanisms of biogenesis and secretion of small extracellular vesicles in non small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1581.
Abstract 5450: New se-nsaid hybrid molecules as potent and selective cytotoxic agents against breast cancer cells
Authors: Sandra Ramos-Inza, Ignacio Encío, Asif Raza, Arun Sharma, Carmen Sanmartín, Daniel Plano
Journal: Cancer Research (2022)

Abstract Breast cancer is currently the most frequently diagnosed cancer and one of the leading causes of mortality among women worldwide. The introduction of a selenium atom (Se) in the structure of organic molecules has been demonstrated to be a valid approach in the design of novel chemotherapeutic agents with several biological effects, including antitumoral activity. In addition, several epidemiological, preclinical, and clinical studies support the chemopreventive and chemotherapeutic potential use of non-steroidal anti-inflammatory drugs (NSAIDs).On the basis of these findings, and taking into account the results of previous studies by our research group, we have developed a new series of twenty-five NSAID analogs bearing Se in the form of selenoesters modulated with different functional groups. The new compounds were tested in four cancer cell lines (HTB-54, DU-145, HT-29 and MCF-7) and two non-malignant cells (184B5 and BEAS-2B). The cytotoxicity of the five most potent and selective molecules was further studied in other cancer cell lines as well. Compounds 4a and 4d stood out as the most selective compounds with a selectivity index at least 5-fold higher in breast cancer cells. Compound 4d showed IC50 values below 10 µM and was found to be more potent than 4a in almost every cell line tested. Additionally, 4d effectively induced apoptosis in triple negative (MDA-MB-231) and estrogen receptor-positive (MCF-7) breast cancer cell lines. Taken together, this study supports the design of new derivatives containing Se as potential anticancer agents. Citation Format: Sandra Ramos-Inza, Ignacio Encío, Asif Raza, Arun Sharma, Carmen Sanmartín, Daniel Plano. New se-nsaid hybrid molecules as potent and selective cytotoxic agents against breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5450.
Abstract 4205: Staged anti-PD-1 therapy with intratumoral recombinant calreticulin improves anti-tumor immunity and survival in glioblastoma mouse models
Authors: Suchet Taori, Breanna Noffsinger, Charlotte A. Miller, Aizhen Xiao, Laryssa Manigat, Qing Zhong, Tajie Harris, Benjamin Purow
Journal: Cancer Research (2022)

Abstract Background: Glioblastoma (GBM), the most common and lethal primary brain tumor, has a median survival of a mere 15 months and leads to approximately 12,000 deaths in the US annually. Targeted and combinatorial-based clinical trial therapies have shown poor efficacy in GBM treatment, partly due to the restrictive nature of the blood-brain barrier, an immunosuppressive tumor microenvironment, GBM’s heterogeneity and adaptability, and GBM’s ability to metastasize and invade critical regions of the brain. However, promising recent literature has indicated that neoadjuvant anti-PD-1 checkpoint-inhibition immunotherapy - i.e., starting it right before surgery for recurrence - improves survival outcomes in human GBM patients. Results: Here, we demonstrate a proposed mechanism of action wherein localized intratumoral danger-associated molecular pattern (DAMP, a known immunogenic driver) injection of calreticulin - used to mimic natural DAMP release from necrotic cells during surgery - combined with neoadjuvant anti-PD-1 immunotherapy leads to better survival outcomes in both orthotopic mouse CT2A and CT2A-Luc GBM models. This survival benefit is also seen in a more aggressive (larger tumor inoculation size) orthotopic CT2A-Luc GBM model. Flow cytometry indicates increased microglia cell counts and activation marker expression, and increased myeloid activation marker expression in mice brains treated with our combination immunotherapy in a CT2A GBM model. Additionally, in vivo treatment with our combination immunotherapy led to increases in the local T and NK cell numbers, the CD8:CD4 ratio, and the proliferation of CD4 T cells in mice brains of a CT2A GBM model. In vitro results suggest that co-culture with CT2A cells increased PD-1 expression in macrophages and microglia and that our combination treatment of calreticulin and anti-PD-1 immunotherapy reduces the viability of mouse GBM cells when mixed with macrophages. Significance: This project paves the path for a novel immunotherapeutic approach to tackle GBM and other cancers. Future studies could incorporate relevant DAMP’s into nanoparticles for sustained release after intratumoral injection and possibly viral delivery of DAMP’s that are constitutively secreted, thereby prolonging an anticipated immune response. Citation Format: Suchet Taori, Breanna Noffsinger, Charlotte A. Miller, Aizhen Xiao, Laryssa Manigat, Qing Zhong, Tajie Harris, Benjamin Purow. Staged anti-PD-1 therapy with intratumoral recombinant calreticulin improves anti-tumor immunity and survival in glioblastoma mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4205.
Abstract 1513: FASN inhibition-induced BRCAness as a therapeutic option for castration-resistant prostate cancer (CRPC)
Authors: Caroline Fidalgo Ribeiro, Silvia D. Rodrigues, Debora C. Bastos, Hubert Pakula, Giorgia Zadra, Marco Foiani, Massimo Loda
Journal: Cancer Research (2022)

Abstract Androgen deprivation therapy (ADT) is the primary treatment for prostate cancer. However, resistance to ADT invariably develops, leading to castration-resistant prostate cancer (CRPC). Prostate cancer progression is marked by overexpression of fatty acid synthase (FASN) and increased de novo synthesis of fatty acids. Importantly, the majority of normal tissues have low expression of FASN and rely mostly on exogenous lipids, making FASN an interesting therapeutic target for prostate cancer. Previously our group evaluated the effects of inhibiting FASN in prostate cancer, with especially promising results in CRPC models. We observed that FASN inhibition decreases DNA damage repair capability by transcriptionally modulating homologous recombination (BRCAness) and non-homologous end joining repair pathways, which leads to increased DNA damage and apoptosis. Key enzymes involved in DNA repair pathways are reduced at the protein level, and the addition of exogenous palmitate, the product of FASN, is able to rescue their expression to normal levels. Interestingly, genes involved in the synthesis of ceramide are upregulated after FASN blockade, with consequent increased cellular levels of ceramides, dihydroceramides and sphingomyelin. Additionally, we observed increased acyl chain unsaturation levels in these lipid species, in line with the uptake of polyunsaturated fatty acids (PUFA) observed when de novo lipogenesis is blocked. The inhibition of ceramide synthesis, both through genetic knock-down with siRNA or pharmacologically with an inhibitor of serine palmitoyltransferase, is capable of partially rescuing the DNA damage induced by FASN inhibition, suggesting a role of ceramides in DNA damage response modulation. Next, we investigated the synergistic effect of combining FASN inhibitor with PARP inhibitor and observed a higher inhibition of cell growth in prostate cancer cell lines in comparison to either drug alone. Human CRPC organoids when treated with PARP and FASN inhibitor in combination showed reduced diameter, as well as reduced cell proliferation, when compared with each agent alone. Overall, our data demonstrate that targeting de novo lipogenesis can increase the therapeutic efficacy of PARP inhibitors and benefit prostate cancer patients that do not harbor BRCA mutations, by pharmacologically downregulating DNA damage repair pathways, particularly HR. Citation Format: Caroline Fidalgo Ribeiro, Silvia D. Rodrigues, Debora C. Bastos, Hubert Pakula, Giorgia Zadra, Marco Foiani, Massimo Loda. FASN inhibition-induced BRCAness as a therapeutic option for castration-resistant prostate cancer (CRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1513.
Abstract 5564: QLS31901, a novel bifunctional anti-PD-L1/TGF-β fusion protein for treatment of solid tumors
Authors: Jiahua Jiang, Cuicui Han, Qi Chen, Yun Wu, Xiaodan Yan, Ping Cao
Journal: Cancer Research (2022)

Abstract Immunosuppressive pathway blocking antibodies (e.g., anti-programmed death ligand 1 [PD-L1] antibodies) are effective and feasible cancer therapy, but some patients have poor individual drug responses to this class of drugs. Simultaneous targeting other immunosuppressive pathways is therefore a novel method to enhance the efficacy. While the antitumor activity of bifunctional anti-PD-L1/transforming growth factor-β (TGF-β) fusion protein bintrafusp alfa (M7824) in preclinical studies is well known, clinical studies to date with M7824 have led to limited success. QLS31901 is another bifunctional fusion protein composed of the truncated extracellular domain of the TGF-β receptor II fused to the C-terminus of humanized anti-PD-L1 heavy chain (αPD-L1) with function as a “trap” for all three TGF-β isoforms and the blockage of PD-L1 immunosuppressive pathway. The present study demonstrated its superior antitumor activity over M7824 in a humanized MDA-MB-231 model. Furthermore, toxicology studies of QLS31901 only showed a transient interleukin 6 elevation. There were no other cytokine release and organ toxicity in cynomolgus monkeys. Overall, these data provided a rationale for an expansion cohort study of QLS31901 for the treatment of patients with solid tumors and dual blockade of TGF-β as well as PD-L1 with QLS31901 may be a promising therapy. Citation Format: Jiahua Jiang, Cuicui Han, Qi Chen, Yun Wu, Xiaodan Yan, Ping Cao. QLS31901, a novel bifunctional anti-PD-L1/TGF-β fusion protein for treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5564.
Abstract 6129: Investigate the mechanism and treatment efficacy of regorafenib combined with anti-PD-L1 on bladder cancer
Authors: Kai-Jen Pai, Yuan Chang, I-Tsang Chiang, Fei-Ting Hsu
Journal: Cancer Research (2022)

Abstract Bladder cancer is one of the most common cancer in urinary system in Taiwan. According to Ministry of Health and Welfare’s research, bladder cancer plays 15th leading causes of death in Taiwan in 2020. The patients who suffer from bladder cancer after undergoing resection surgery about 60% will relapse, and 80% of them will relapse in less than a year, 15% of the relapsing patients will aggravate and become invasive carcinoma spread all over the body. PD-L1 (Programmed death-ligand 1), also known as B7-H1 and CD274 is a transmembrane glycoprotein, which interacts with PD-1 (Programmed death-1) receptor on T cells to elicit the immune checkpoint response. Overexpression of PD-L1 suppresses the function of CD8+ T cells and facilitate tumor progression. Targeting tumor PD-L1 may be a possible treatment option; however, PD-L1 expression was only detected in small amount of population. Regorafenib is a multiple tyrosine kinase inhibitor, which has been approved by the US Food and Drug Administration to treat advanced HCC. In our research, we found that regorafenib may upregulation the surface PD-L1 expression in both mice and human cell line. Based on this finding, we suggested that regorafenib may show potential to enhance treatment efficacy anti-PD-L1. Therefore, we established MB-49 bearing animal model to identify the immune regulation and treatment efficacy of regorafenib combined with anti-PD-L1. In ours animal data we found that combination therapy effectively increased the tumor infiltrating population of NK cells and CD8+ lymphocytes which were determined by flow cytometry assay. Not only anti-tumoral leukocytes, we also detected the population of immune suppressor cells including regulatory T cells, MDSCs and M2 macrophage was suppressed by combination therapy. We also detected the tumor microenvironment related markers (VEGF, IDO-1, PD-L1, CD8, CD31, CD49b, FOXP3, granzyme B) to evaluate combination therapy effect by using immunohistochemistry staining. In conclusion, regorafenib may effectively enhance anti-PD-L1 efficacy via triggering positive immune regulation and increasing the interaction of anti-PD-L1 with tumor. Citation Format: Kai-Jen Pai, Yuan Chang, I-Tsang Chiang, Fei-Ting Hsu. Investigate the mechanism and treatment efficacy of regorafenib combined with anti-PD-L1 on bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6129.